PET imaging of beta-secretase 1 in the human brain. Radiation dosimetry, quantification, and test-retest examination of [${}^{18}$F]PF-06684511

Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [${}^{18}$F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [${}^{18}$F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [${}^{18}$F]PF-06684511 in healthy volunteers. Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (V${}_T$) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of V${}_T$ were calculated as reliability measures. In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. V${}_T$ (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of V${}_T$ (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644). The ED of [${}^{18}$F]PF-06684511 was similar to other ${}^{18}$F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of V${}_T$ was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [${}^{18}$F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain.